BRD4 localization to lineage-specific enhancers is associated with a distinct transcription factor repertoire.
BRD4 localization to lineage-specific enhancers is associated with a distinct transcription factor repertoire.
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DOI：
10.1093/nar/gkw826
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发表时间：
2017-01-09
影响因子：
14.9
通讯作者：
Johnsen SA
中科院分区：
文献类型：
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作者：
Najafova Z;Tirado-Magallanes R;Subramaniam M;Hossan T;Schmidt G;Nagarajan S;Baumgart SJ;Mishra VK;Bedi U;Hesse E;Knapp S;Hawse JR;Johnsen SA
基因表达的适当时间表观遗传调控对于细胞命运决定和组织发育是必不可少的。含溴结构域蛋白-4（BRD 4）先前显示控制各种细胞系统中的基因的限定子集的转录。在这项研究中，我们研究了BRD 4在促进谱系特异性基因表达中的作用，并表明BRD 4对成骨细胞分化至关重要。全基因组分析表明，BRD 4被募集到分化诱导基因的转录起始位点。出乎意料的是，虽然启动子近端BRD 4占用与基因表达相关，但显示中等表达和启动子近端BRD 4占用的基因对BRD 4抑制最高度调节和敏感。因此，我们检查了远端BRD 4占有率，并发现了BRD 4与转录因子C/EBPb、TEAD 1、FOSL 2和JUND在推定的成骨细胞特异性增强子处的特异性共定位。这些发现揭示了谱系特化的复杂性，并为BRD 4的上下文相关功能提供了新的见解。
Proper temporal epigenetic regulation of gene expression is essential for cell fate determination and tissue development. The Bromodomain-containing Protein-4 (BRD4) was previously shown to control the transcription of defined subsets of genes in various cell systems. In this study we examined the role of BRD4 in promoting lineage-specific gene expression and show that BRD4 is essential for osteoblast differentiation. Genome-wide analyses demonstrate that BRD4 is recruited to the transcriptional start site of differentiation-induced genes. Unexpectedly, while promoter-proximal BRD4 occupancy correlated with gene expression, genes which displayed moderate expression and promoter-proximal BRD4 occupancy were most highly regulated and sensitive to BRD4 inhibition. Therefore, we examined distal BRD4 occupancy and uncovered a specific co-localization of BRD4 with the transcription factors C/EBPb, TEAD1, FOSL2 and JUND at putative osteoblast-specific enhancers. These findings reveal the intricacies of lineage specification and provide new insight into the context-dependent functions of BRD4.